Semisynthetic Derivatives of Perovskone: Development of a Promising Class of Antiprotozoal Lead Compounds.

Abstract

Perovskones, intricate triterpenoids with potent antiplasmodial activity, predominantly derive from Salvia hydrangea DC. ex Benth. In this study, ample quantities of the parent compound, perovskone (1), were isolated from the plant. Using perovskone (1) as a feedstock, seven semisynthetic analogues (2-8) were generated via reactions like hydroxylation, elimination, and esterification. Structural characterization was performed by using 1D and 2D NMR, HRMS, and X-ray diffraction experiments. The compounds underwent in vitro antiparasitic testing against Leishmania donovani, Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Trypanosoma cruzi. Cytotoxicity evaluation was performed using rat myoblast (L6) cells. Perovskone (1) demonstrated excellent activity against T. cruzi, showing an IC₅₀ value of 0.89 μM and a selectivity index (SI) of 14.9. Perovskone I (4) and perovskone G (2) exhibited potent activity against P. falciparum (IC₅₀ values of 0.03 and 0.08 μM, respectively), with favorable SIs of 843.0 and 80.0, comparable to those of chloroquine and artemisinin. Perovskone M (8) displayed promising antileishmanial activity (IC₅₀ = 0.44 μM, SI = 22), comparable to the efficacy of miltefosine against L. donovani (IC₅₀ = 0.51 μM). We believe that the current study holds immense potential for the development of promising leads in antiplasmodial drug discovery.